The Transmembrane Domain of the Molecular Chaperone Cosmc Directs Its Localization to the Endoplasmic Reticulum

• Type of Material: Article
• Authors: Qian Sun, Emory University; Tongzhong Ju, Emory University; Richard Cummings, Emory University
• Language: English
• Date: 2011-04-01
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://www.jbc.org/content/286/13/11529
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 286
• Issue: 13
• Start Page: 11529
• End Page: 11542
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grant R01 GM068559 (to R. D. C.).
• Keywords: Endoplasmic Reticulum (ER); Glycosylation; Protein Folding; Cosmc; Plasma Membrane; Localization; Protein Chimeras; T-synthase; Protein Sorting; Golgi
• Research Categories: Chemistry, Biochemistry

Abstract

The molecular basis for retention of integral membrane proteins in the endoplasmic reticulum (ER) is not well understood. We recently discovered a novel ER molecular chaperone termed Cosmc, which is essential for folding and normal activity of the Golgi enzyme T-synthase. Cosmc, a type II single-pass transmembrane protein, lacks any known ER retrieval/retention motifs. To explore specific ER localization determinants in Cosmc we generated a series of Cosmc mutants along with chimeras of Cosmc with a non-ER resident type II protein, the human transferrin receptor. Here we show that the 18 amino acid transmembrane domain (TMD) of Cosmc is essential for ER localization and confers ER retention to select chimeras. Moreover, mutations of a single Cys residue within the TMD of Cosmc prevent formation of disulfide-bonded dimers of Cosmc and eliminate ER retention. These studies reveal that Cosmc has a unique ER-retention motif within its TMD and provide new insights into the molecular mechanisms by which TMDs of resident ER proteins contribute to ER localization.